Hepatitis B virus (HBV) infection afflicts as many as 300 million people worldwide. In the United States alone, 200,000 new cases of HBV infection occur annually. Many individuals who are chronically infected with HBV develop associated pathologies such as chronic hepatic insufficiency, cirrhosis, and hepatocellular carcinoma. Currently available HBV treatment are quite unsatisfactory. For example, alpha-Interferon has only limited efficacy, and Lamivudine selects for resistant virus in more than 14% of treated individuals within one year. Most anti-HBV nucleoside analogues are toxic due to incorporation into mitochondrial DNA. Moreover, HBV quickly develops resistance to antiviral nucleosides when used as single agents. There is an urgent need for better anti-HBV nucleosides for use in combination therapy. Recently, at Novirio Pharmaceuticals, Inc., the L-enantiomers of natural thymidine (i.e., L-thymidine) were found to be active against HBV in vitro and in chronically infected woodchucks. This is a unique nucleoside which is a mirror image of the natural nucleoside and has no effect on mitochondrial function. Further development, however, has been hampered due to the lack of an efficient procedure for large-scale preparation of this nucleoside. Novirio Pharmaceutical is a strategic partner of Pharmasset, Inc., and they depend on us for development of process chemistry. Therefore, we plan to develop facile methods of large-scale synthesis of each of L-nucleosides counterparts of all four naturally-occurring 2'- deoxynucleosides in Phase I. The synthesized L-nucleosides will be studied, in collaboration with Novirio, for further anti- HBV evaluation and early toxicological studies. In Phase II, we will select the most promising nucleoside and manufacture a sufficient quantity to carry out in vivo pharmacological and advanced toxicological evaluations using the woodchuck model in collaboration with Novirio leading to IND. Phase III will be focused on an IND application and clinical studies in collaboration with Novirio. This part of drug development will be discussed in more details in the Phase II application. PROPOSED COMMERCIAL APPLICATIONS: In the US 200,000 new cases of HBV infection occur annually. About 1-2% of these cases develop fulminant hepatitis with a mortality rate of 60-70%. Six to ten percent of infected patients progress to chronic active hepatitis. About 6,000 people in the US die from HBV cirrhosis and HBV-related liver cancer. This number is growing, which indicates that more effective treatments are needed. Worldwide millions of chronically infected patients need be treated.